Enhanced Characterization of Drug Metabolism and the Influence of the Intestinal Microbiome: A Pharmacokinetic, Microbiome, and Untargeted Metabolomics Study.

Determining factors that contribute to interindividual and intra-individual variability in pharmacokinetics (PKs) and drug metabolism is essential for the optimal use of drugs in humans. Intestinal microbes are important contributors to variability; however, such gut microbe-drug interactions and the clinical significance of these interactions are still being elucidated. Traditional PKs can be complemented by untargeted mass spectrometry coupled with molecular networking to study the intricacies of drug metabolism. To show the utility of molecular networking on metabolism we investigated the impact of a 7-day course of cefprozil on cytochrome P450 (CYP) activity using a modified Cooperstown cocktail and assessed plasma, urine, and fecal data by targeted and untargeted metabolomics and molecular networking in healthy volunteers. This prospective study revealed that cefprozil decreased the activities of CYP1A2, CYP2C19, and CYP3A, decreased alpha diversity and increased interindividual microbiome variability. We further demonstrate a relationship between the loss of microbiome alpha diversity caused by cefprozil and increased drug and metabolite formation in fecal samples. Untargeted metabolomics/molecular networking revealed several omeprazole metabolites that we hypothesize may be metabolized by both CYP2C19 and bacteria from the gut microbiome. Our observations are consistent with the hypothesis that factors that perturb the gut microbiome, such as antibiotics, alter drug metabolism and ultimately drug efficacy and toxicity but that these effects are most strongly revealed on a per individual basis

Probing shock geometry via the charge to mass ratio dependence of heavy ion spectra from multiple spacecraft observations of the 2013 November 4 event

In large Solar Energetic Particle (SEP) events, ions can be accelerated at coronal mass ejection (CME)-driven shocks to very high energies. The spectra of heavy ions in many large SEP events show features such as roll-overs or spectral breaks. In some events when the spectra are plotted in terms of energy/nucleon, they can be shifted relative to each other to make the spectral breaks align. The amount of shift is charge to mass ratio (Q/A) dependent and varies from event to event. This can be understood if the spectra of heavy ions are organized by the diffusion coefficients (Cohen et al. 2005). In the work of Li et al. (2009), the Q/A dependence of the scaling is related to shock geometry when the CME-driven shock is close to the Sun. For events where multiple in-situ spacecraft observations exist, one may expect that different spacecraft are connected to different portions of the CME-driven shock that have different shock geometries, therefore yielding different Q/A dependence. In this work, we examine one SEP event which occurred on 2013 November 4. We study the Q/A dependence of the energy scaling for heavy ion spectra using helium, oxygen and iron ions. Observations from STEREO-A, STEREO-B and ACE are examined. We find that the scalings are different for different spacecraft. We suggest that this is because ACE, STEREO-A and STEREO-B are connected to different parts of the shock that have different shock geometries. Our analysis indicates that studying the Q/A scaling of in-situ particle spectra can serve as a powerful tool to remotely examine the shock geometry for large SEP events

UJI AKTIVITAS PROTEASE DAN KARAKTERISASI PH ACTINOMYCETES ISOLAT ATH-03 ASAL TAHURA POCUT MEURAH INTAN KABUPATEN ACEH BESAR

ABSTRAKKata kunci: Aktivitas Protease, Karakterisasi pH, Actinomycetes.Penelitian Uji Aktivitas Protease dan Karakterisasi pH Actinomycetes Isolat ATH-03 Asal Tahura Pocut Meurah Intan Kabupaten Aceh Besar telah dilaksanakan sejak tanggal 3 September sampai dengan 27 Desember 2012. Penelitian ini bertujuan untuk mengukur aktivitas protease dan mengetahui pH optimum aktivitas protease dari isolat Actinomycetes ATH-03. Metode penelitian yang digunakan adalah metode Eksperimen dengan Rancangan Acak Lengkap Non Faktorial dengan 6 kali perlakuan, 2 kali ulangan. Data yang diperoleh dianalisis secara deskriptif yang terkait dengan nilai indeks proteolitik sebagai dasar seleksi isolat Actinomycetes. Isolat Actinomycetes berasal dari koleksi Laboratorium Mikrobiologi Jurusan Biologi FMIPA Universitas Syiah Kuala. Delapan belas isolat Actinomycetes menunjukkan aktivitas pada Media NA yang mengandung susu skim 1%. Isolat ATH-03 dipilih dalam penelitian ini karena memiliki zona bening yang lebar dengan indeks proteolitik (IP) tertinggi 8,537 setelah inkubasi selama 48 jam pada Media NAS. Protease ekstraseluler dikarakterisasi menggunakan media NB yang mengandung susu skim 1% sebagai media produksi. Waktu optimum pemanenan ekstrak kasar protease isolat ATH-03 pada hari ke-7 dengan aktivitas sebesar 0,083 U/ml, kadar protein 0,003 mg/ml dan aktivitas spesifik mencapai 23,72 U/mg. Hasil karakterisasi pH ekstrak kasar enzim isolat ATH-03 menunjukkan aktivitas optimum pada pH 8 yaitu 0,067 U/ml, protease yang dihasilkan oleh isolat ini aktif pada kisaran pH netral.Banda Ace

What low back pain is and why we need to pay attention

Low back pain is a very common symptom. It occurs in high-income, middle-income, and low-income countries and all age groups from children to the elderly population. Globally, years lived with disability caused by low back pain increased by 54% between 1990 and 2015, mainly because of population increase and ageing, with the biggest increase seen in low-income and middle-income countries. Low back pain is now the leading cause of disability worldwide. For nearly all people with low back pain, it is not possible to identify a specific nociceptive cause. Only a small proportion of people have a well understood pathological cause—eg, a vertebral fracture, malignancy, or infection. People with physically demanding jobs, physical and mental comorbidities, smokers, and obese individuals are at greatest risk of reporting low back pain. Disabling low back pain is over-represented among people with low socioeconomic status. Most people with new episodes of low back pain recover quickly; however, recurrence is common and in a small proportion of people, low back pain becomes persistent and disabling. Initial high pain intensity, psychological distress, and accompanying pain at multiple body sites increases the risk of persistent disabling low back pain. Increasing evidence shows that central pain-modulating mechanisms and pain cognitions have important roles in the development of persistent disabling low back pain. Cost, health-care use, and disability from low back pain vary substantially between countries and are influenced by local culture and social systems, as well as by beliefs about cause and effect. Disability and costs attributed to low back pain are projected to increase in coming decades, in particular in low-income and middle-income countries, where health and other systems are often fragile and not equipped to cope with this growing burden. Intensified research efforts and global initiatives are clearly needed to address the burden of low back pain as a public health problem

A decade of monitoring on Pool 26 of the upper Mississippi River System: water quality and fish data from the Upper Mississippi River Restoration Environmental Management Program

We present information gleaned from 10 years of data collected by the water quality component of the Upper Mississippi River Restoration Environmental Management Program’s Long Term Resource Monitoring Program (LTRMP) from Pool 26 of the Upper Mississippi River System (UMRS). The Pool 26 reach of the UMRS includes the confluence with the Illinois River, and the confluence with the Missouri River just downstream of Mel Price Locks and Dam. The surrounding communities in both Illinois and Missouri benefit greatly from the natural resources provided by these rivers. We estimate that annual expenditures are 55 million for fishing and hunting, respectively, in the region surrounding Pool 26 based on license sales and state expenditure data from the U.S. Fish and Wildlife Service. Additionally, there is a commercial fishery active in Pool 26, recreational boating, and the UMRS provides drinking water for many municipalities in this region. Finally, the Upper Mississippi River System is a major transportation system, and Pool 26 receives the greatest amount of barge traffic for any river reach in the UMRS. The LTRMP began collecting data in 1988, but the first years of the program were experimental. Currently followed monitoring protocols for water quality and fish monitoring were adopted in 1993; however, a major flood event in that year prevented full data collection for that year. Data from the LTRMP water quality component demonstrate that Pool 26 is a highly productive river reach. Long-term averages of chorophyll-a, total phosphorous, total nitrogen, and total inorganic solids are comparable to levels in eutrophic to highly eutrophic lakes. The average current velocity in the main channel of the Mississippi River in Pool 26 ranges from 0.364–0.414 m/sec. during the summer and fall. Even during the lowest discharge levels in a year, the reach has a residence time no longer than 2.7 days. Discharge was significantly related to many water quality parameters, including Secchi depth, turbidity, total suspended solids, total nitrogen, nitrate-nitrite, and total phosphorus. We observed a significant linear increase in mean water temperature in the main channel from 1994 to 2004. When these data were analyzed by season, positive linear trends were found during the spring (0.515°C per year) and fall (0.646°C per year). Continued monitoring is necessary to determine if these observations represent short term fluctuations or long-term trends and to detect any related effects on this river reach

Phenotypic Characterization of EIF2AK4 Mutation Carriers in a Large Cohort of Patients Diagnosed Clinically With Pulmonary Arterial Hypertension.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a rare disease with an emerging genetic basis. Heterozygous mutations in the gene encoding the bone morphogenetic protein receptor type 2 (BMPR2) are the commonest genetic cause of PAH, whereas biallelic mutations in the eukaryotic translation initiation factor 2 alpha kinase 4 gene (EIF2AK4) are described in pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Here, we determine the frequency of these mutations and define the genotype-phenotype characteristics in a large cohort of patients diagnosed clinically with PAH. METHODS: Whole-genome sequencing was performed on DNA from patients with idiopathic and heritable PAH and with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis recruited to the National Institute of Health Research BioResource-Rare Diseases study. Heterozygous variants in BMPR2 and biallelic EIF2AK4 variants with a minor allele frequency of <1:10 000 in control data sets and predicted to be deleterious (by combined annotation-dependent depletion, PolyPhen-2, and sorting intolerant from tolerant predictions) were identified as potentially causal. Phenotype data from the time of diagnosis were also captured. RESULTS: Eight hundred sixty-four patients with idiopathic or heritable PAH and 16 with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis were recruited. Mutations in BMPR2 were identified in 130 patients (14.8%). Biallelic mutations in EIF2AK4 were identified in 5 patients with a clinical diagnosis of pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Furthermore, 9 patients with a clinical diagnosis of PAH carried biallelic EIF2AK4 mutations. These patients had a reduced transfer coefficient for carbon monoxide (Kco; 33% [interquartile range, 30%-35%] predicted) and younger age at diagnosis (29 years; interquartile range, 23-38 years) and more interlobular septal thickening and mediastinal lymphadenopathy on computed tomography of the chest compared with patients with PAH without EIF2AK4 mutations. However, radiological assessment alone could not accurately identify biallelic EIF2AK4 mutation carriers. Patients with PAH with biallelic EIF2AK4 mutations had a shorter survival. CONCLUSIONS: Biallelic EIF2AK4 mutations are found in patients classified clinically as having idiopathic and heritable PAH. These patients cannot be identified reliably by computed tomography, but a low Kco and a young age at diagnosis suggests the underlying molecular diagnosis. Genetic testing can identify these misclassified patients, allowing appropriate management and early referral for lung transplantation

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Surgical site infection after gastrointestinal surgery in high-income, middle-income, and low-income countries: a prospective, international, multicentre cohort study

Background: Surgical site infection (SSI) is one of the most common infections associated with health care, but its importance as a global health priority is not fully understood. We quantified the burden of SSI after gastrointestinal surgery in countries in all parts of the world. Methods: This international, prospective, multicentre cohort study included consecutive patients undergoing elective or emergency gastrointestinal resection within 2-week time periods at any health-care facility in any country. Countries with participating centres were stratified into high-income, middle-income, and low-income groups according to the UN's Human Development Index (HDI). Data variables from the GlobalSurg 1 study and other studies that have been found to affect the likelihood of SSI were entered into risk adjustment models. The primary outcome measure was the 30-day SSI incidence (defined by US Centers for Disease Control and Prevention criteria for superficial and deep incisional SSI). Relationships with explanatory variables were examined using Bayesian multilevel logistic regression models. This trial is registered with ClinicalTrials.gov, number NCT02662231. Findings: Between Jan 4, 2016, and July 31, 2016, 13 265 records were submitted for analysis. 12 539 patients from 343 hospitals in 66 countries were included. 7339 (58·5%) patient were from high-HDI countries (193 hospitals in 30 countries), 3918 (31·2%) patients were from middle-HDI countries (82 hospitals in 18 countries), and 1282 (10·2%) patients were from low-HDI countries (68 hospitals in 18 countries). In total, 1538 (12·3%) patients had SSI within 30 days of surgery. The incidence of SSI varied between countries with high (691 [9·4%] of 7339 patients), middle (549 [14·0%] of 3918 patients), and low (298 [23·2%] of 1282) HDI (p < 0·001). The highest SSI incidence in each HDI group was after dirty surgery (102 [17·8%] of 574 patients in high-HDI countries; 74 [31·4%] of 236 patients in middle-HDI countries; 72 [39·8%] of 181 patients in low-HDI countries). Following risk factor adjustment, patients in low-HDI countries were at greatest risk of SSI (adjusted odds ratio 1·60, 95% credible interval 1·05–2·37; p=0·030). 132 (21·6%) of 610 patients with an SSI and a microbiology culture result had an infection that was resistant to the prophylactic antibiotic used. Resistant infections were detected in 49 (16·6%) of 295 patients in high-HDI countries, in 37 (19·8%) of 187 patients in middle-HDI countries, and in 46 (35·9%) of 128 patients in low-HDI countries (p < 0·001). Interpretation: Countries with a low HDI carry a disproportionately greater burden of SSI than countries with a middle or high HDI and might have higher rates of antibiotic resistance. In view of WHO recommendations on SSI prevention that highlight the absence of high-quality interventional research, urgent, pragmatic, randomised trials based in LMICs are needed to assess measures aiming to reduce this preventable complication

A decade of monitoring on Pool 26 of the upper Mississippi River System : water quality and fish data from the Upper Mississippi River Restoration Environmental Management Program

Abstract: We present information gleaned from 10 years of data collected by the water quality component of the Upper Mississippi River Restoration Environmental Management Program’s Long Term Resource Monitoring Program (LTRMP) from Pool 26 of the Upper Mississippi River System (UMRS). The Pool 26 reach of the UMRS includes the confluence with the Illinois River, and the confluence with the Missouri River just downstream of Mel Price Locks and Dam. The surrounding communities in both Illinois and Missouri benefit greatly from the natural resources provided by these rivers. We estimate that annual expenditures are $84 and$55 million for fishing and hunting, respectively, in the region surrounding Pool 26 based on license sales and state expenditure data from the U.S. Fish and Wildlife Service. Additionally, there is a commercial fishery active in Pool 26, recreational boating, and the UMRS provides drinking water for many municipalities in this region. Finally, the Upper Mississippi River System is a major transportation system, and Pool 26 receives the greatest amount of barge traffic for any river reach in the UMRS. The LTRMP began collecting data in 1988, but the first years of the program were experimental. Currently followed monitoring protocols for water quality and fish monitoring were adopted in 1993; however, a major flood event in that year prevented full data collection for that year. Data from the LTRMP water quality component demonstrate that Pool 26 is a highly productive river reach. Long-term averages of chorophyll-a, total phosphorous, total nitrogen, and total inorganic solids are comparable to levels in eutrophic to highly eutrophic lakes. The average current velocity in the main channel of the Mississippi River in Pool 26 ranges from 0.364–0.414 m/sec. during the summer and fall. Even during the lowest discharge levels in a year, the reach has a residence time no longer than 2.7 days. Discharge was significantly related to many water quality parameters, including Secchi depth, turbidity, total suspended solids, total nitrogen, nitrate-nitrite, and total phosphorus. We observed a significant linear increase in mean water temperature in the main channel from 1994 to 2004. When these data were analyzed by season, positive linear trends were found during the spring (0.515°C per year) and fall (0.646°C per year). Continued monitoring is necessary to determine if these observations represent short term fluctuations or long-term trends and to detect any related effects on this river reach.is peer reviewe

Comprehensive Rare Variant Analysis via Whole-Genome Sequencing to Determine the Molecular Pathology of Inherited Retinal Disease

Inherited retinal disease is a common cause of visual impairment and represents a highly heterogeneous group of conditions. Here, we present findings from a cohort of 722 individuals with inherited retinal disease, who have had whole-genome sequencing (n = 605), whole-exome sequencing (n = 72), or both (n = 45) performed, as part of the NIHR-BioResource Rare Diseases research study. We identified pathogenic variants (single-nucleotide variants, indels, or structural variants) for 404/722 (56%) individuals. Whole-genome sequencing gives unprecedented power to detect three categories of pathogenic variants in particular: structural variants, variants in GC-rich regions, which have significantly improved coverage compared to whole-exome sequencing, and variants in non-coding regulatory regions. In addition to previously reported pathogenic regulatory variants, we have identified a previously unreported pathogenic intronic variant in $\textit{CHM}$ in two males with choroideremia. We have also identified 19 genes not previously known to be associated with inherited retinal disease, which harbor biallelic predicted protein-truncating variants in unsolved cases. Whole-genome sequencing is an increasingly important comprehensive method with which to investigate the genetic causes of inherited retinal disease.This work was supported by The National Institute for Health Research England (NIHR) for the NIHR BioResource – Rare Diseases project (grant number RG65966). The Moorfields Eye Hospital cohort of patients and clinical and imaging data were ascertained and collected with the support of grants from the National Institute for Health Research Biomedical Research Centre at Moorfields Eye Hospital, National Health Service Foundation Trust, and UCL Institute of Ophthalmology, Moorfields Eye Hospital Special Trustees, Moorfields Eye Charity, the Foundation Fighting Blindness (USA), and Retinitis Pigmentosa Fighting Blindness. M.M. is a recipient of an FFB Career Development Award. E.M. is supported by UCLH/UCL NIHR Biomedical Research Centre. F.L.R. and D.G. are supported by Cambridge NIHR Biomedical Research Centre